Inhibitors of farnesyl-protein transferase

- Merck & Co., Inc.

The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.

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Claims

1. A compound of formula I: ##STR11## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1a, R.sup.1b, R.sup.2 and R.sup.10 are independently selected from the group consisting of: hydrogen, aryl, substituted aryl,C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, NO.sub.2, (R.sup.8).sub.2 NC(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2, R.sup.9 OC(O)NR.sup.8 -- and C.sub.1 -C.sub.6 alkyl, unsubstituted or substituted with 1-3 groups selected from the group consisting of: halo, aryl, heterocyclyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, (R.sup.8).sub.2 NC(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2 and R.sup.9 OC(O)NR.sup.8 --;

R.sup.3 and R.sup.4 are independently selected from the group consisting of: H, F, Cl, Br, --N(R.sup.8).sub.2, CF.sub.3, NO.sub.2, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NH--, H.sub.2 NC(NH)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, CN, R.sup.9 OC(O)NR.sup.8 --, C.sub.1 -C.sub.20 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl;
A.sup.1 and A.sup.2 are independently selected from the group consisting of: a bond, --CH.dbd.CH--, --C.tbd.C--, --C(O)--, --C(O)NR.sup.8 --, --NR.sup.8 C(O)--, --O--, --N(R.sup.8)--, --S(O).sub.2 N(R.sup.8)--, --N(R.sup.8)S(O).sub.2 --, and S(O).sub.m;
A.sup.3 is selected from the group consisting of: --C(O)--, --O--, --S(O).sub.m --, --OC(O)--, --C(O)O--, --NR.sup.5 --, --NR.sup.5 S(O).sub.m -- or S(O).sub.m NR.sup.5 --;
A.sup.4 is selected from --O--, --S(O).sub.m --, --NR.sup.5 --, --NR.sub.5 C(O)--, --C(O)NR.sup.5 --, --OC(O)--, --C(O)O--, --NR.sup.5 S(O).sub.m -- and --S(O).sub.m NR.sup.5 --;
m represents 0, 1 or 2;
each R.sup.5 is independently selected from the group consisting of: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C.sub.3 -C.sub.10 cycloalkyl, and C.sub.1 -C.sub.6 alkyl unsubstituted or substituted with 1-3 members selected from the group consisting of: unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C.sub.3 -C.sub.10 cycloalkyl, N(R.sup.8).sub.2, CF.sub.3, NO.sub.2, (R.sup.8)O--, (R.sup.9)S(O).sub.m --, (R.sup.8)C(O)NH--, H.sub.2 N--C(NH)--, (R.sup.8)C(O)--, (R.sup.8)OC(O)--, N.sub.3, CN (R.sup.9)OC(O)NR.sup.8 --;
R.sup.6 and R.sup.7 are independently selected from the group consisting of: hydrogen, aryl, heterocyclyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1-6 perfluoroalkyl, F, Cl, Br, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, NO.sub.2, (R.sup.8).sub.2 NC(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2, R.sup.9 OC(O)NR.sup.8 -- and C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by 1-3 groups selected from: aryl, heterocyclyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, perfluoroalkyl, F, Cl, Br, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, (R.sup.8).sub.2 NC(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2 and R.sup.9 OC(O)NR.sup.8 --;
each R.sup.8 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, aryl and aralkyl;
each R.sup.9 is independently selected from C.sub.1 -C.sub.6 alkyl and aryl;
V is selected from the group consisting of: hydrogen, heterocyclyl, aryl, C.sub.1 -C.sub.20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and C.sub.2 -C.sub.20 alkenyl, provided that V is not hydrogen if A.sup.1 is S(O).sub.m and V is not hydrogen if A.sup.1 is a bond, n is 0 and A.sup.2 is S(O).sub.m;
W is imidazolyl or imidazolinyl;
Y represents aryl;
each n and p independently represents 0, 1, 2, 3 or 4;
q is 1, 2, 3 or 4;
r is 0 to 5, provided that r is 0 when V is hydrogen, and
t is 0 or 1.

2. A compound in accordance with claim 1 wherein R.sup.1a,R.sup.1b, R.sup.2 and R.sup.10 are independently selected from: hydrogen, --N(R.sup.8).sub.2, R.sup.8 C(O)NR.sup.8 -- or unsubstituted or substituted C.sub.1 -C.sub.6 alkyl, wherein the substituent on the substituted C.sub.1 -C.sub.6 alkyl is selected from unsubstituted or substituted aryl, --N(R.sup.8).sub.2, R.sup.8 O-- and R.sup.8 C(O)NR.sup.8 --.

3. A compound in accordance with claim 1 wherein R.sup.3 and R.sup.4 are selected from: hydrogen and C.sub.1 -C.sub.6 alkyl.

4. A compound in accordance with claim 1 wherein R.sup.6 is selected from CN, NO.sup.2 or R.sup.8 O--.

5. A compound in accordance with claim 1 wherein R.sup.7 represents hydrogen, unsubstituted or substituted C.sub.1 -C.sub.6 alkyl.

6. A compound in accordance with claim 1 wherein R.sup.8 represents H or C.sub.1-6 alkyl, and R.sup.9 is C.sub.1-6 alkyl.

7. A compound in accordance with claim 1 wherein A.sup.1 and A.sup.2 are independently selected from: a bond, --C(O)NR.sup.8 --, --NR.sup.8 C(O)--, --O--, --N(R.sup.8)--, --S(O).sub.2 N(R.sup.8)-- and --N(R.sup.8)S(O).sub.2 --.

8. A compound in accordance with claim 1 wherein A.sup.3 represents O, S, NR.sup.5 or NR.sup.5 S(O).sub.m, wherein m represents 2 and R.sup.5 represents hydrogen.

9. A compound in accordance with claim 1 wherein A.sup.4 represents --C(O)NR.sup.5 -- or --NR.sup.5 C(O)--, with R.sup.5 representing H.

10. A compound in accordance with claim 1 wherein V is selected from hydrogen, heterocyclyl and aryl.

11. A compound in accordance with claim 1 wherein V is phenyl.

12. A compound in accordance with claim 1 wherein m is 0 or 2.

13. A compound in accordance with claim 1 wherein n and p are 0, 1, 2 or 3.

14. A compound in accordance with claim 1 wherein t is 1.

15. A subset of compounds of the invention is represented by formula Ia: ##STR12## wherein: R.sup.3, R.sup.4, A.sup.3, A.sup.4, Y, R.sup.8, R.sup.9, m, n, p and r are as originally defined;

each R.sup.1a, R.sup.1b, R.sup.2 and R.sup.10 is independently selected from hydrogen and C.sub.1 -C.sub.6 alkyl;
R.sup.5 is selected from the group consisting of: hydrogen and C.sub.1 -C.sub.6 alkyl, unsubstituted or substituted with 1-3 members selected from the group consisting of: unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C.sub.3 -C.sub.10 cycloalkyl, --N(R.sup.8).sub.2, --CF.sub.3, --NO.sub.2, (R.sup.8)O--, (R.sup.9)S(O).sub.m --, (R.sup.8)C(O)NH--, H.sub.2 NC(NH)--, (R.sup.8)C(O)--, (R.sup.8)OC(O)--, N.sub.3, CN and (R.sup.9)OC(O)NR.sup.8 --;
R.sup.6 and R.sup.7 are independently selected from: hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, R.sup.8 O--, R.sup.8 C(O)NR.sup.8 --, CN, NO.sub.2, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --, and C.sub.1 -C.sub.6 alkyl substituted by C.sub.1 -C.sub.6 perfluoroalkyl, R.sup.8 O--, R.sup.8 C(O)NR.sup.8 --, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, --N(R.sup.8).sub.2 and R.sup.9 OC(O)NR.sup.8 --;
A.sup.1 and A.sup.2 are independently selected from: a bond, --CH.dbd.CH--, --C.tbd.C--, --C(O)--, --C(O)NR.sup.8 --, O, --N(R.sup.8)-- and S(O).sub.m;
and V is selected from: hydrogen; aryl; heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl and thienyl; C.sub.1 -C.sub.20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and C.sub.2 -C.sub.20 alkenyl, provided that V is not hydrogen if A.sup.1 is S(O).sub.m and V is not hydrogen if A.sup.1 is a bond and A.sup.2 is S(O).sub.m.

16. A compound in accordance with claim 1 represented by formula Ia: ##STR13## wherein: R.sup.1a, R.sup.1b, R.sup.2, R.sup.10, A.sup.1, A.sup.2, A.sup.4, Y, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.8, R.sup.9, m, n, p, q and r are as originally defined;

R.sup.7 is selected from: hydrogen and C.sub.1 -C.sub.6 alkyl;
A.sup.3 represents --S--;
V is selected from: hydrogen, heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, aryl, C.sub.1 -C.sub.20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and C.sub.2 -C.sub.20 alkenyl,

17. A compound in accordance with claim 1 represented by formula Ic: ##STR14## wherein: each R.sup.1b and R.sup.10 is independently selected from hydrogen and C.sub.1 -C.sub.6 alkyl;

R.sup.3, R.sup.4, R.sup.8, R.sup.9, m, p, and q are as originally defined;
A.sup.3 represents --O--, --S-- or --NH--;
A.sup.4 represents --C(O)NH-- or --NHC(O)--;
and R.sup.6 is selected from the group consisting of: hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, R.sup.8 O--, R.sup.8 C(O)NR.sup.8 --, CN, NO.sub.2, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 -- and C.sub.1 -C.sub.6 alkyl substituted by C.sub.1 -C.sub.6 perfluoroalkyl, R.sup.8 O--, R.sup.8 C(O)NR.sup.8 --, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, --N(R.sup.8).sub.2 or R.sup.9 OC(O)NR.sup.8 --.

18. A compound in accordance with claim 1 having the structural formula: ##STR15## or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition which is comprised of a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.

20. A method of treating cancer in a mammalian patient in need of such treatment, comprising administering to said patient an anti-cancer effective amount of a compound of claim 1.

21. A method for inhibiting farnesyl-protein transferase in a mammalian patient in need of such treatment, which comprises administering to said mammal a farnesyl-protein transferase inhibiting amount of a compound of claim 1.

22. A method for treating neurofibromin benign proliferative disorder which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1.

23. A method for treating blindness related to retinal vascularization which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1.

24. A method for treating infections from hepatitis delta and related viruses which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1.

25. A method for preventing restenosis which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1.

26. A method for treating polycystic kidney disease which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1.

27. A method for treating or preventing a disease selected from cancer, neurofibromin benign proliferative disorder, blindness related to retinal vascularization, infections from hepatitis delta and related viruses, restenosis and polycystic kidney disease, which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1.

28. A method of treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1.

Referenced Cited
U.S. Patent Documents
5576313 November 19, 1996 Fisher et al.
Foreign Patent Documents
96/30343 October 1996 WOX
96/37204 November 1996 WOX
Other references
  • Exp. Opin. Ther. Patents, vol. 5(12), pp. 1269-1271 (1995), by S. L. Graham. Exp. Opin. Ther. Patents, vol. 6(12) (1996), p. 12951304, by S. L. Graham et al. J. of Biol. Chem., vol. 268, No. 11, pp. 7617-7620 (1993), by J. B. Gibbs, et al. J. of Biol. Chem., vol. 269, No. 44, pp. 27706-27714 (1994), by G. L. James, et al. J. of Biol. Chem., vol. 270, No. 11, pp. 6221-6226 (1995), by G. L. James, et al. Science, vol. 260, pp. 1934-1937 (1993), by N. E. Kohl, et al. Proc. Natl. Acad. Sci. USA, vol. 91, pp. 9141-9145 (1994), by N. E. Kohl, et al. Nature Medicine, vol. 1, No. 8, pp. 792-797 (1995), by N. E. Kohl, et al. Cancer Research, vol. 55, pp. 5302-5309 (1995), by L. Sepp-Lorenzino, et al .
Patent History
Patent number: 5925651
Type: Grant
Filed: Apr 1, 1997
Date of Patent: Jul 20, 1999
Assignee: Merck & Co., Inc. (Rahway, NJ)
Inventor: John H. Hutchinson (Philadelphia, PA)
Primary Examiner: Johann Richter
Assistant Examiner: Ebenezer Sackey
Attorneys: Diane Pecoraro, David A. Muthard, Mark R. Daniel
Application Number: 8/834,675
Classifications
Current U.S. Class: Isoquinolines (including Hydrogenated) (514/307); 514/2278; Additional Hetero Ring Attached Directly Or Indirectly To The Quinoline Ring System By Nonionic Bonding (514/314); The Additional Ring Is A Hetero Ring (514/326); Chalcogen Bonded Directly To Ring Carbon Of The Piperidine Ring (514/327); C=x Bonded Directly To The Piperidine Ring (x Is Chalcogen) (514/330); The Additional Hetero Ring Consists Of Two Nitrogens And Three Carbons (514/341); Additional Hetero Ring (514/444); Chalcogen Bonded Directly To Ring Carbon Of The Hetero Ring (514/445); Nitrogen Bonded Directly To The Hetero Ring (514/447); C=o Bonded Directly To The Hetero Ring (x Is Chalcogen) (514/448); 546/2727; Having -c(=x)-, Wherein X Is Chalcogen, Bonded Directly To The Six-membered Hetero Ring (546/156); Plural Ring Nitrogens In The Additional Hetero Ring (546/210); Plural Chalcogens Bonded Directly To Ring Carbons Of Each Of The Two Nitrogen Containing Hetero Rings (e.g., Bis-succinimides, Etc.) (548/520); 548/3365; Nitrogen Bonded Directly To Chalcogen (548/197); Chalcogen Bonded Directly To Ring Carbon Of The Five-membered Hetero Ring (e.g., 3-indolols, Etc.) (548/484); Nitrogen Attached Directly To The Hetero Ring By Nonionic Bonding (549/63); Having -c(=x)-, Wherein X Is Chalcogen, Bonded Directly To The Hetero Ring (549/64); Nitrogen Attached Indirectly To The Hetero Ring By Nonionic Bonding (549/65); Chalcogen Attached Indirectly To The Hetero Ring By Nonionic Bonding (549/66); Oxygen Bonded Directly To The Carbonyl (e.g., Benzoic Acid Esters, Etc.) (558/416)
International Classification: A61K 3147; A61K 3144; C07D23361; C07C25504;